Beta-substituted alpha, beta-diphenylethylamines and the preparation thereof



Patented Apr. 11, 1950 amazes BETA-SUBSTITUTED ALPHAJSETA-DI- PHENYLETHYLAMINES AND THE PREPARATION THEREOF Warren D. McPhee, C'astleton-on-Hudson, N. Y.,

assignor, by mesne assignments, to Winthrop- Stearns Inc., New York, N. Y., a corporation of Delaware No Drawing. Application October 18, 1945, Serial No. 623,174

9 Claims.

This invention relates to a,p-diphenylethylamines and salts thereof, wherein the B- phenyl nucleus is substituted with hydroxyl and alkoxyl radicals, and to methods of preparing the same. In particular it relates to a-phenyl- J3 (3-alkoxy-4-hydroxyphenyl)ethylamines and salts thereof, and to processes of preparing the same.

The object of this invention is to provide new compositions of matter which are useful for therapeutic purposes, due to their valuable analgesic and other therapeutic properties. A further object of this invention is to provide new medicinal preparations having analgesic action which are suited for treatment of humans and animals.

In general the new compositions which are the basis of this invention are e-phenyl-s-(alkoxyhydroxyphenyl)ethylamines, having the following formula:

no NH:

and water-soluble salts thereof, wherein R represents a lower alkyl group. A preferred specific embodiment of the invention comprises aphenyl 7 9 (3-methoXy-4-hydroxyphenyl) ethylamine hydrochloride.

In a preliminary survey, Dodds, Lawson and Williams [Nature, 151, 6-14 (1943); Proc. Roy. Soc. (London), B, 132, 119 (1944)] reported that certain diphenylethylamines and related compounds relieve pain due to pressure on the nerves of humans with inoperable tumors. In a later note by the same workers .[Nature, 154, 514 (1944)] it is stated that the diphenylethylamines and related compounds previously tested clinically are entirely devoid of analgesic activity when tested by the electric shock method on rats. The compounds which had been used clinically have a specific action on nerve pressure pain, but no general analgesic effect. The series of diphenylethylamines tested by the English workers did not, however, include those in which the a-phenyl radical is unsubstituted and in which the B-phenyl radical is substituted with hydroxyl and alkcxyl groups.

I have discovered that a-phenyl-B-(alkoxyhydroxyphenyDethylamines and salts thereof produce general analgesic in humans and animals. This discoverey is surprising in light of the disclosure of Dodds, Lawson and Williams [Nature, 154, 514 (1944)] that diphenylethylamines and salts thereof produce no universal analgesic effeet.

The amines which are the basis of this invention may be employed either in the form of the free bases or in the form of salts. For parenteral administration it is desirable that the compositions be soluble in water. For this purpose the hydrochlorides of the bases are suitable. Other acids may be used in preparing salts of the amines, among them being sulfuric, citric, lactic and tartaric. The term salts is used herein to include any salt of an u-fi-diphenylethylamine, wherein the 8-phenyl nucleus is substituted with hydroxyl and alkoxyl radicals, with any acid the anion of which is tolerated in therapeutic dosages.

A possible theoretical explanation of the fact that the ufi-diphenylethylamines having in the fi-phenyl nucleus hydroxyl and alkoxyl radicals are physiologically active and exert an analgesic effect whereas the 00,13 diphenylethylamines which are not substituted in such a manner have no analgesic action may be that the former group of compounds resemble morphine more closely than the latter, in that morphine has a 4-hydroxyl group and a 3-ether group in the aromatic ring which corresponds to the B-phenyl nucleus of the a,,6-diphenylethylamines.

The method used for the preparation of u.- plhenyl-s- (alkoxyhydroxyphenyl) ethylamines is outlined in the following series of equations and illustrated in the appended examples. It is apparent that any aromatic aldehyde bearing hydroxyl and alkoxyl substituents may be used in preparing the desired u-phenyl-fi-(hydroxyalkoxyphenyhethylamines and salts thereof without departing from the spirit and scope of my invention. The following examples are merely illustrative and in no way limit my invention.

washed thoroughly with water. One hundred and sixty-six grams (94% yield) of white powder,

CeHsCHaOQ- It is further apparent to those skilled in the art that the intermediate a-phenyl-B-(hydroxyalkoxyphenyl) propionic acids can be converted to a. phenyl B (hydroxyalkoxyphenyl) ethylamines by other reactions than the I-loimann reaction, which comprises conversion of the acid to the corresponding amide and treatment with hypohalite in alkaline solution. For example, the Curtius reaction or the Lossen reaction can be used. In the former, the acid is converted to the corresponding azide which decomposes into an amine or an amine derivative. In the latter a hydroxamic acid is prepared from the carboxylic acid and it rearranges upon decomposition, forming an amine or derivative thereof.

Example 1 A. a Phenyl 3-methoxy-4-hydroarycinnamic acid-A solution of 131 g. (0.86 mole) of vanillin and 150 g. (0.95mole) of sodium phenylacetatein 600 cc. (5.38 moles) of acetic anhydride is refluxed for'five hours. One hundred and fifty cubic centimeters (8.33 moles) of water is added dropwise to the solution at a rate sufiicient tomaintain-the solution at reflux. Upon cooling, 2. tan solid separates and is washed thoroughly with water. The tan solid is dissolved in 1800 cc. of 6% sodium hydroxide and the solution refluxed for one hour. Acidification of this solution to pH 2 with concentrated hydrochloric acid yields 137 g. (59% yield) of slightly yellow solid, M. P. 186-187 C. Ecf. Dey and Row, Quart. J. Indian Chem, Soc, 1, 277 (1925)].

B. a-Phenyl-fl- (3-methoscy--hydrozcyphenyl) propionic acid-A solution of 175.8 g. (0.65 mole) of a-phenyl-Za-methoxy-4-hydroxycinnamic .acid in an equivalent amount of sodium carbonate is diluted to 860 cc. with water. The reduction is carried out at 300-450 lbs/sq. in hydrogen pressure and 100 C. with Raney nickel catalyst and requires four hours. After removal of the catalyst, the solution is acidified to pH .2. with 4 N hydrochloric acid. The white precipitate is NeOH H R0 CHa-CHNH: HOQCHPCH- I PdC R=lower alky M. P. 142-143 C. is obtained. Calculated for Ciel-D604: C, 70.42; H, 5.92. Found: C, 70.42; H, 5.91.

C. a Phenyl c (3 methory 4 benzyloxyphenyl) propionic acid.-A mixture 0f'1l8 g. (0.434 mole) of a phenyl 8-(3-methoxy-4-hydroxyphenyl) propionic acid, 195 g. (1.54 moles) (148 cc.) of benzyl chloride, 3.5 g. (0.021 mole) of potassium iodide, 17.4 g. (0.435 mole) of sodium hydroxide in 100 cc. of water, and 500 cc. of ethanol is brought to reflux. Refluxing is continued for three hours, during which time a 1 solution of 86.8 g. (2.17 moles) of sodium hydroxide in 300 cc. of water is added dropwise with stirring. The solution is refluxedan additional hour. It is evaporated to one-half its original volume and 500 cc. of water 'is added. The aqueous solution is extracted with ether, then acidified to pI-I2 with 4 N hydrochloric acid. The solid which precipitates is recrystallized from 50 aqueous methanol; yield, g. (64%); M. P. 114-115 C. Calculated for C23H22O4: C, 76.22; H, 6.12. Found: C, 76.19; H, 6.31.

D. a Phenyl I8 (3 methoxy 4-benzyloscyphenyl) propionamide.A mixture of 8'7 .1 g. (0.24 mole) of a-phenyl-c-(3-methoxy-4-benzyloxyphenyl propionic acid and 150 cc. (2.25 mole) of thionyl chloride is refluxed for ten minutes. The excess thionyl chloride is removed in vacuo, and the residue is dissolved in 500 cc. of anhydrous dioxane. The dioxane solution is added dropwise with vigorous stirring to 1 liter of concentrated ammonium hydroxide. The white precipitate is washed thoroughly with water and airdried. A yield of 77.6,g. (89%) is obtained; M. 1. -142 C. Recrystallization from ethyl acetate gives a .M. P. of 142143 C. Calculated for C23H2303N: 'N, 3.88. Found: N, 3.93.

E. a Phenyl ,8 (3 methory -.4-benzyloa:yphenyl) ethylamine hydrochloride.-A mixture of 74.0 g. (0205 mole) of a-phenyl-p-(il-methoxy- 4-benzyloxyphenyl)propionamide, 274 cc. of.40% sodium hydroxide, 42.7 g. (0.267 mole) of bromine and 500 cc. of water is refluxed for two hours. Upon cooling, the alkaline solution is extracted with ether, the extract dried over anhydrous sodium sulfate and the hydrochloride precipitated with ethereal hydrogen chloride. The 61.1 g. of brown-orange solid, M. P. 193-196 C. is triturated with 100 cc. of hot ethyl acetate to yield 51 gm. (67%) of light yellow solid, M. P. 199-200 C. A sample recrystallized from methanol-dioxane melts at 203-204 C. Calculated for C22I-I24O2NCl: N, 3.97. Found: N, 3.84.

F. a Phenyl ,9 (3 methoxy 4 hydroxyphenybethylamine hydrochZoride.-Fifty grams (0.135 mole) of a-phenyl-p-(3-methoxy-4-benzyloxyphenyl) ethylamine hydrochloride is dissolvedin 400 cc. of hot methanol. The solution is hydrogenated in two portions at 55 and -60 lbs/sq. in. hydrogen pressure in the presence of palladium-on-charcoal catalyst. After removal of the catalyst, the solution is evaporated to dryness in vacuo. The residue is washed well with ether, resulting in 37.5 g. (99%) of a slightly tan solid, M. P. 219-220 C. with sintering at 218 C. after recrystallization from methanol-ethyl acetate, the purified product melted at 219-220 C. Calculated for C15l-I180zNCl: N, 5.01. Found: N, 5.11.

G. a Phenyl 6 (3 methowy 4 hydroxyphenyZ)ethylamine.-An aqueous solution of a-phenyl-fl- (3-methoxy-4-hydroxyphenyl) ethylamine hydrochloride is brought to pH 7 with di-- lute alkali. The turbid mixture is extracted four times with ether and the ether extracts dried with anhydrous sodium sulfate. Evaporation of the ether leaves a yellow solid. This is triturated with petroleum ether of B. P. -90" C.; the resulting product being a light yellow powder. Crystallization of this powder from a mixture of benzene and petroleum ether of B. P. 60-90 C. gives crystals of a-phenyl-fl-(3-methoxy-4-hydroxyphenyDethylamine having a M. P. of 138-140 C.

Example 2 A. a-Phenyl- 3- ethoscy 4 hydroavycinnamic acid-This acid is made as shown in Example 1A, using 3 ethoxy 4 hydroxy-benzaldehyde, commonly known as ethyl vanillin. It melts at 186-186.5 C., after recrystallization from methanol. Calculated for CHI-11604: C, 71.81; H, 5.67. Found: C, 71.83; H, 5.38.

B. a-Phenz/Z-B-(3-eth0my 4 hydroxyphenyl) propiom'c acid.-Catalytic hydrogenation of o.- phenyl-3-ethoxyl-hydroxycinnamic acid in dilute sodium carbonate solution in the presence of Raney nickel, followed by removal of catalyst and acidification, as in Example 1B, results in nearly the theoretrical yield of u-pheny1-6(3- ethoxy-4-hydroxyphenyl)propionic acid, which melts at 144-146 C. Calculated for C17H1804I C, 71.31; H, 6.34. Found: C, 71.40: H, 6.06.

C. a. PhenyZ-c-(3-etho:cy-4-benzylomyphenyl) propiomc acid, is made by benzylating a-phenylfi-(3 ethoxy 4 hydroxyphenyl) propionic acid with benzyl chloride in alkaline solution, according to the method set forth. in Example 10. It melts at 105-106 C. Calculated for 024112404: C, 76.57; H, 6.44. Found: C, 76.58; H, 6.53.

D. a-Phenyl-B-(3ethomy-4 henzyloxyphenyl) propionamz'de is prepared by the method given in Example 1D, using thionyl chloride and aqueous ammonia. It melts at 139-140 C. Calculated for C24H2503N2 N, 3.73. Found: N, 3.67.

E. a-Phenyl-B-(3-ethoxy-4 benzyloznyphenyl) ethylamine hydrochloride is made by the Hofmann reaction according to the general method given in Example 1E. It melts at 207-208 C. Calculated for C23I-I2eO2NC1: N, 3.65. Found: N, 3.62.

F. a-PhenyZ-fi-(3-ethowy 4 hydroxyphenyl) ethylamine hydrochloride-The product of Example 1E is catalytically debenzylated in methanol in the presence of palladium-on-charcoal catalyst. Removal of the catalyst and evaporation of the solvent leaves yellow crystals. Recrystallization from methanol diluted with ethyl acetate gives colorless crystals of M. P. 217-218 C. Calculated for CmI-IzoOzNCl: N, 4.77. Found: N, 4.82.

In addition to the methods shown in the above equations and examples, a, p-diphenylethylamines having substituents in the fi-phenyl nucleus can be made by the catalytic reduction of suitably substituted a'-nitrostilbenes. For example, 3 methoxy 4 hydroxy-d-nitrostilbene may be reduced in methanol solution in the presence of palladium-on-charcoal catalyst to aphenyl-p-(S-methoxy 4 hydroxyphenyl) ethylamine, as shown in the following equation:

Similarly, 3 methoxy 4-benzyloxy-d-nitrostilbene may be reduced to a-phenyl-p-(S-methoXy- 4-hydroxyphenyl)ethylamine. The substituted a'-nitrostilbenes are prepared by condensing substituted benzaldehydes with phenylnitromethane in basic solution.

WhatIclaim is:

1. An a,;3-diphenylethylamine containing in the fi-phenyl nucleus hydroxyl and lower alkoxyl substituents and salts thereof, said amine and salts thereof having analgesic properties.

2. An a-phenyl-p-(3-alkoxy-4-hydroxyphenyl) ethylamine and salts thereof, said amine and salts thereof having analgesic properties.

3. a-PheIlYl-fl-(3-Ili8thOXY-4 hydroxyphenyl) ethylamine and salts thereof, said amine and salts thereof having analgesic properties.

4. a-Phenyl-s-(3-methoxy-4 hydroxyphenyl) ethylamine hydrochloride, having analgesic properties.

5. a-Phenyl-e-(3 ethoxy 4 hydroxyphenyl) ethylamine and salts thereof, said amine and salts thereof having analgesic properties.

6. a-Phenyl-p-(3 ethoxy 4 hydroxyphenyl) ethylamine hydrochloride, having analgesic properties.

7. A process for the preparation of an aphenyl-B-aryl-ethylamine which comprises reacting an a-phenyl-p-arylpropionamide devoid of aromatic hydroxyl groups with an alkali metal hypohalite in alkaline solution.

8. In a process for the preparation of an aphenyl 5 (hydroxyalkoxyaryl) ethylamine, the step which comprises converting an a-phenyl- 8- (benzyloxyalkoxyaryl)propionamide into an aphenyl p (benzyloxyalkoxyaryl) ethylamine by reaction with sodium hypobromite in the presence of sodium hydroxide.

9. A process for the preparation of an aphenyl-5-(3-alkoxy 4 hydroxyphenyDethylamine which comprises reacting an a-phenyl-e- (3 alkoxy 4 benzyloxyphenyl)propionamide with sodium hypobromite in the presence of sodium hydroxide and debenzylating by catalytic hydrogenolysisithe resultant aephenyl-B- (3*- OTHER REFERENCES: alkxy4*benzyloxyphenyvethylamme- Reichert et a1 Chem Absts' vol 30 columns WARREN MCPHEE- 5580-5582 (1936). Chem. Absts., v01. 33, page 8182 (1940). REFEEENCES CITED 5 Ser. No. 419,811, K1112 (A. P. 0.), published The following references-are of =record 1n the April 20, 1943 fil of "this patent: Dodds et al., Nature, Vol. 151, p. 614511943).

UNITED STATES PATENTS I Dodds et al., Nature, vol. 154, p. 514 (1944).

Organic Chemistry, Fieser & Fieser, pp. 232233" Number- Name Date 10 1944),

$047,144 Kharasch' July "7; 1936 

1. A A,B-DIPHENYLETHYLAMINE CONTAINING IN THE B-PHENYL NUCLEUS HYDROXYL AND LOWER ALKOXYL SUBSTITUENTS AND SALTS THEREOF, SAID AMINE AND SALTS THEREOF HAVING ANALGESIC PROPERTIES. 